Individuals with neurofibromatosis type 1 (NF1) are predisposed to certain cancers including juvenile chronic myelogenous leukaemia (JCML). The NF1 tumour-suppressor gene encodes a protein (neurofibromin) that accelerates GTP hydrolysis on Ras proteins. Here we show that primary leukaemic cells from children with NF1 show a selective decrease in NF1-like GTPase activating protein (GAP) activity for Ras but retain normal cellular GAP activity. Leukaemic cells also show an elevated percentage of Ras in the GTP-bound conformation. JCML cells are hypersensitive to granulocyte-macrophage colony stimulating factor (GM-CSF), and we observed a similar pattern of aberrant growth in haematopoietic cells from Nf1-/- mouse embryos. These data define a specific role for neurofibromin in negatively regulating GM-CSF signaling through Ras in haematopoietic cells and they suggest that hypersensitivity to GM-CSF may be a primary event in the development of JCML.

IN OUR OPINION a comprehensive schema for descnption of the much discussed "total personality" is a pnme requirement in psydiology at this time The reasons for this need will be elaborated upon below, but may be stated bnefly as follows (1) Current conceptual systems in psychology usually emphasize only one of several areas of personality or one type of datum, e g, manifest or behavioral traits, central urges, psychodiagnostic categones, etc, and relationships among different areas and levels are but imperfectly dealt with, if at all (2) Most variables m current use in the field of psychology lack clear or systematic interpersonal reference(3) For the most part concepts oriented toward psycho-pathological functioning are emphasized, while those deahng with normal functioning are neglected (4) Many personality vanables in current use are not so stated or defined as to permit their objective measurementThis IS the first of a series of articles designed to present a comprehensive schema for the orgamzation of personality data The system to be described presents an account of the "total personality" based on a tripartite division of personahty data (le, the "total personality" is described by the nature of the data in each of three ' The studies on which this paper is based have been sponsored by Permanente Foundation Hospital, Oakland, California, under the codirection of Hubert S Coffey, Ph.D, and Harvey Powelson, M D The current expanded research pro}a:t >s in part supported by the U S Public Health Service under the direction of Saxton T Pope, Jr, M D The authors are grateful to Dr Jean Walker Macfarlane for her editorial contributions to this article A four-year collaborative research study involving 20Q subjects has provided the data aa which the theones of variables presented in this article are tased. For each subject there were available for study the protocols of ten personality tests and approximately cne thousand verbal interactions obtained by &e wire recording of group psychotherapy sessions.

Beginning chelation treatment with deferoxamine before the age of puberty can help children with transfusion-dependent thalassemia major to attain normal sexual maturation.

Deferoxamine is widely used therapeutically as a chelator of ferric ion in disorders of iron overload. This study demonstrates that this drug is a potent inhibitor of DNA synthesis by human B and T lymphocytes in vitro, but has relatively little effect on the synthesis of RNA and protein. The inhibitory effects of deferoxamine are completely reversible by washing or by adding stoichiometric amounts of Fe3+. Micromolar concentrations of deferoxamine decrease intracellular levels of deoxyribonucleoside triphosphates, which is similar to the effects of hydroxyurea. The binding of iron by deferoxamine likely causes an inhibition of ribonucleotide reductase activity, thereby preventing cells from completing the S phase of the cell proliferation cycle. As a reversible and nontoxic S-phase inhibitor, it may have important experimental and therapeutic applications.

A six week old infant with acute leukemia failed to attain remission with chemotherapy. Because we previously demonstrated that the iron chelator deferoxamine (DFO) has antiproliferative properties and modulatory effects on cell differentiation, a protocol was designed for in vitro study and for clinical use in the patient. At diagnosis, blast cells were morphologically undifferentiated, had nondiagnostic cytochemistry, showed an abnormal karyotype (t[4;11]), expressed markers of B cell lineage, and demonstrated C mu gene rearrangement. Tissue culture of marrow or blood cells yielded colonies of leukemic blasts. Increasing concentrations of DFO produced a dose-dependent suppression of patient's blast colony growth in vitro, and blasts within colonies showed a marked change in surface antigen expression from lymphoid to myelomonocytic markers, became monocytic in appearance, and developed intense staining for nonspecific esterase. When DFO was given intravenously to the patient as a single agent for 48 hours, blasts no longer expressed lymphoid antigens and became strongly positive for myelomonocytic markers, identical to the in vitro findings. Intravenous DFO halted rising peripheral blood blast cell numbers and allowed a several-fold increase in normal hematopoietic progenitor colony growth. When combined with low-dose cytosine arabinoside in the treatment protocol, DFO caused striking leukemic cytoreduction. Our findings indicate that DFO has antileukemic properties by virtue of its effects on proliferation and differentiation, and they prompt further experimental and clinical studies with this agent.

Shwachman-Diamond syndrome is an autosomal recessive disorder characterized by exocrine pancreatic dysfunction, bony metaphyseal dysostosis, various degrees of cytopenia, and a striking tendency to develop myelodysplastic syndrome and acute myeloblastic leukemia. Isochromosome 7 [i(7q)] is a rare non-random cytogenetic abnormality of myeloid cells in hematological malignancy. We report two cases of Shwachman-Diamond syndrome in which patients developed myelodysplastic syndrome and i(7q), detected by G-banding karyotype analysis and fluorescence in situ hybridization. Three other children have been previously reported to have myelodysplastic syndrome in association with i(7q); two of them had Shwachman-Diamond syndrome. Isochromosome 7q may be a fairly specific marker of myeloid malignant transformation in this syndrome and play a role in its pathogenesis.

Summary:for more than 20 years. [1][2][3][4][5] Early studies in children, using the standard total adult busulphan dose of 16 mg/kg, reported decreased toxicity, increased graft rejection and Busulphan (BU) pharmacokinetic (PK) studies in children undergoing bone marrow transplantation suggest increased neoplastic relapse in children compared to adults. [2][3][4][5][6][7][8][9][10][11] Subsequent pharmacokinetic studies have conthat individual BU dosing may be necessary to optimise BU systemic exposure. Optimising BU systemic firmed that, at this dose, children achieve significantly lower busulphan systemic exposure as measured by the area exposure may improve outcome and decrease toxicity in BMT. Because of practical limitations in obtaining under the curve (AUC) of busulphan vs time. [12][13][14][15][16][17][18][19][20] Busulphan dosing, based on surface area, in children (busulphan blood from children and for financial reasons, a limited sampling method (LSM) is needed. However, such 600 mg/m 2 ) has been associated with BU AUCs that were similar to adults and with acceptable toxicity, but the wide methods for BU have not been validated in children. In the present study, we individualized oral BU dosing in inter-patient variability in AUCs persists. 14-18 Age, disease, circadian rhythms, food, drugs and pretransplant liver 10 children to target an area under the curve of BU (BU AUC) of 900-1400 M/min based on BU AUC 0-ؕ abnormalities have been identified as causes of variability in busulphan disposition. 20calculated from nine serum BU concentrations performed after a BU test dose of 40 mg/m 2 . We validated a Grochow 19 reported an increased risk of hepatic venoocclusive disease (VOD) in patients whose AUC was LSM using 3 BU concentrations to determine AUC. Six of nine patients studied (one patient non-evaluable), greater than 1500 m/min and a reduction in the risk of VOD in adults who received dose adjustment to target an required their doses modified (3, lower; 3, higher). The mean percent dose change was 26.2% (range −33.3% to AUC 900-1500 m/min. Many authors have suggested that individual busulphan +45.3%). Our three sample LSM BU AUC 0-ؕ (1098 ± 344, mean ± 1 s.d.) correlated highly with our dosing based on therapeutic drug monitoring may be necessary to achieve maximal busulphan systemic exposure nine sample BU AUC 0-ؕ (1132 ± 389, Pearson r = 0.98, P = 0.0001) and was not significantly different by t-test while minimising toxicity. [18][19][20][21] To this end, we initiated a study of individualising busulphan dosing based on meas-(P = 0.3). The mean percentage difference between the three sample LSM AUCs and the nine sample AUCs in ured BU AUC, with an intended target range of 900 to 1400 m/min. each of our patients was 7.5%, (range −10.99% to +9.4%). Trough levels correlated extremely well withIn most centers nine to 12 blood samples are drawn to derive BU AUC. This frequency of blood sampling, even AUC (r = 0.95, P = 0.0001). Individual BU dosing, based on AUC, is necessary in most children to ach...

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